Each of the wells shown above contains information about which genes are active in different sections of the human genome. The experiment revealed clusters of genes that work together in development of a fetus or a cancer tumor. (Staff photos Justin Ide/Harvard News Office)

Protein packages found to activate genes

May be what regulates development and disease

By William J. Cromie
Harvard News Office

It's all in the packaging. How nature wraps and tags genes determines if and when they become active, according to researchers from Harvard and the Massachusetts Institute of Technology (M.I.T.). They did the largest, most detailed study to date of the protein structure that surrounds the human genome.

Their findings reveal surprising and previously unknown specifics of how genes get switched on during development of the human body and in diseases such as cancer.

"Each type of cell in our bodies contains the same genes. What makes them do different things involves which genes are turned on," notes Bradley Bernstein, a pathologist at Harvard Medical School. He is also a research associate at the Broad Institute of Harvard and M.I.T., where a complex analysis of packaging of two entire human chromosomes was done for the first time.

Besides Bernstein, the investigators included Morris Loeb Professor of Chemistry Stuart Schreiber; Michael Kamal, Eric Lander, and others at the Broad Institute; and their colleagues from Affymetrix, a California technology company.

The analysis shows a striking and surprising exception in the way some critical genes are activated by the protein packaging. These proteins act like spools for the long strings of DNA that contain our genes and form chromosomes. The researchers studied chemical tags that are attached to the spools and switch on the genes they wrap. In most cases, they found these tags turn genes on and off individually. The big surprise involves clusters of so-called "HOX" genes, which apparently work in concert to control how we develop in the womb. Instead of being activated individually like most genes, the HOX genes appear to be turned on in groups by massive numbers of tags.

HOX genes also are deeply involved in cancer, making the findings particularly important. Some of the proteins that regulate HOX genes are capable of causing or suppressing tumors.

Bradley Bernstein (right) works with technician Dana Hubert to find tags in chromatin packaging that indicate which genes are accessible to be turned on.

Technological breakthrough

Bernstein has been studying chromosome wrappings for five years as a postdoctoral researcher in the lab of Stuart Schreiber. Together they worked out techniques to examine the way genes are packaged in yeast. To go from yeast to humans required a technological breakthrough, however.

"Most prior studies involved only single genes, but we wanted to investigate entire chromosomes, which contain hundreds of genes," Bernstein notes.

He and Schreiber enlisted the help of Affymetrix, which makes so-called "gene chips" that rapidly scan millions of small sections of chromosomes to detect gene activity. But the scanning results left them with a huge amount of data, and the daunting task of deciphering what it means in terms of how genes function. For that part of the project, they teamed with investigators from the Broad (pronounced to rhyme with "road") Institute.

"The human genome still has many surprises lurking within it," comments Lander, who is director of the institute. "One of the most important is the mystery of how genes are turned on. The ability to take global views of (chromosome packaging) in human cells holds tremendous promise for unraveling the mystery."

To begin unraveling this mystery, the researchers studied large regions of the genome and identified the DNA sequences associated with chromatin that contains "on" tags. DNA is the same in all the cells in our body. What makes the cells do different jobs is that different genes are turned on. For example, the set of genes turned on in a nerve cell is different from those turned on in muscle, heart, blood, and other cells.

Although the exact ways genes are turned on and off remain unknown, the tags in chromatin are believed to play a major role. Until now, however, it had not even been known which regions of the genome carry such tags.

A complete surprise

Most regions of the chromatin have only a few "on" tags, but in regions packaging clusters of HOX genes hundreds of such tags exist. Yeast cells don't have such clusters, but HOX clusters in mice and humans boast relatively huge sections of chromatin completely covered with tags. This was not seen before by using standard techniques, or by studying one gene at a time. "Finding them was a complete surprise," Bernstein admits.

HOX genes, as noted, play vital roles in embryo development. Understanding how they are regulated should help researchers determine the molecule-by-molecule procedure involved in the assembly of organs and tissues, like brains and muscles, into a complex living organism.

HOX genes are also vital for understanding the way that people get certain cancers. "Many of the proteins that regulate these genes can suppress or enhance tumor growth," Bernstein notes. "Some of the genes can cause cancer directly when altered by mutations."

"The work we're doing now is very fundamental," he says. "But what we learn about the interactions between chromatin, its tags, and various proteins that interact with them may one day be useful for understanding, diagnosing, and even developing new treatments for some cancers."